02203nas a2200193   4500000000100000008004100001100001200042700001500054700001000069700001600079700001500095700001300110700001700123700001500140700001500155245013100170520169400301022001401995       2016                            d1 aYoon GS1 aKeswani RK1 aSud S1 aRzeczycki P1 aMurashov M1 aKoehn TA1 aStandiford T1 aStringer K1 aRosania GR00aClofazimine Biocrystal Accumulation in Macrophages Upregulates IL-1RA Production to Induce a Systemic Anti-Inflammatory State.3 a<p>Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice following 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction of caspase 1 and IL-1β cleavage in the livers of 8 week CFZ-treated mice as compared to 2 week CFZ-treated and control mice, which was accompanied by a three-fold increase in hepatic interleukin 1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1β cleavage and TNFα expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan- and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8 week CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, as CFZ accumulation had minimal effect in IL-1RA knockout mice, or 2 week CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.</p>
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